principles of drug action exam 3 PD AD

Question 1

WHAT IS PARKINSON‘S DISEASE?

Answer 1

Parkinson Disease is a neurodegenerative disorder of the central nervous system (CNS)

Tremor-resting

 Rigidity

 Akinesia/Bradykinesia
 Slowness in initiation and execution of voluntary movements

 Posture and gait
 Shuffling feet with abnormal fixation of posture (stoop when

standing), equilibrium, and righting reflex

Question 2

how does dopamine effect PD

Answer 2

In PD, most of the brain cells that produce dopamine that are located in the substantia nigra have undergone neurodegeneration and died, causing a severe shortage of dopamine in the striatum/basal ganglia.

Question 3

KEY DOPAMINE PATHWAYS

Nigrostriatal system

Answer 3

Nigrostriatal system

Dopamine neurons originating in substantia nigra and terminating in corpus striatum (basal ganglia)

Nigrostriatal Pathway

 Deficiency of dopamine associated with MOVEMENT Disruptions

Question 4

NIGROSTRIATAL PATHWAY AND THE BASALGANGLIA

Answer 4

Group of interconnected forebrain nuclei including:

– Caudate nucleus
– Putamen
– Globus pallidus
– Subthalamic Nucleus

and… closely associated midbrain nuclei:

– Substantia nigra – Thalamus

Question 5

BASAL GANGLIA CIRCUIT AND EFFECTS OFDA

Answer 5

Direct Pathway - Cortex to striatum (GABAergic cells expressing D1 receptors) to Gpi/SNpr to thalamus to cortex

NOTE: presence of DA stimulates this pathway and promotes movement

Indirect pathway- Cortex to striatum (GABAergic cells expressing D2 receptors) to GPe to STN to GPi/SNpr to thalamus to cortex.

NOTE: Presence of DA inhibits this pathway and also promotes movement;

Question 6

WHAT CAUSES PARKINSON’S DISEASE?

Answer 6

Genetic factors
 Parkin, alpha-synuclein, others

 Environmental factors

 Many have been identified, including head injuries and exposure to certain toxins and pesticides.

Early Pathology

-Environmental insults may play a  primary role in patients with PD onset Late

after age 50.

Neuroleptic-induced Parkinsonism: 7% - 9%.

• Phenothiazines
• Butyrophenones
• Reserpine

Question 7

PHARMACOTHERAPY OPTIONS FOR PD

Answer 7

ALL available pharmacotherapy options treat symptoms

 Restore function and quality but over time they are ineffective

 Not effective for dementia and cognitive impairment which occur later in late stages of disease

Dopaminergic agents-attempt to replace dopamine  Levodopa (L-DOPA)
[Dopamine agonists]

DA metabolism inhibitors-managing symptoms

 Decarboxylase inhibitors  Carbidopa

 MAO-B inhibitors  Selegiline

 COMT inhibitors [Entacapone, Tolcapone]

Question 8

SO WHAT DRUGS DO WE USE TO TREAT PD?

Answer 8

Parkinson disease medicines can help control or improve certain symptoms of the disease, such as trouble moving the body, stiffness, and shaking (called “tremors”)

 Currently, no medicines can cure Parkinson disease or keep it from getting worse over time.

Question 9

LEVODOPA (L-DOPA)

Answer 9

Most effective drug for Parkinsonian symptoms.

 Virtually all patients with confirmed PD experience clinically significant benefit.

Question 10

Sites of Action of Parkinson’s Disease Drugs

Answer 10

Levodopa –aadc–> Dopamine to striatum

AADC

• Requires active transport across the blood-brain barrier
• Requires metabolic conversion to dopamine by dopamine decarboxylase (AADC)

3 neurons include

Substantia Nigra :ACh

In Parkinson’s disease, the dopaminergic neurons in the substantia nigra degenerate

striatum : receives glutamatergic and dopaminergic inputs from different sources. In particular, the subthalamic nucleus (STN) becomes overactive and acts as a brake on the globus pallidus interna (GPi), causing shutdown of motion and rigidity

globud pallidus interna: When the GPi is overstimulated, it has an over-inhibitory effect on the thalamus, which in turn decreases thalamus output and causes tremor (Fig. 3).

Question 11

L-DOPA PHARMACOKINETICS

Answer 11

L-Dopa is readily absorbed from GI Tract

• Usually large doses must be given due to First Pass Effect since ~1% actually cross Blood Brain Barrier and enters CNS
• Large amount of L-Dopa has to be given since L- Dopa is also metabolized by dopa decarboxylase in liver and periphery to dopamine.
• Rational for the use of Carbidopa, increases the bioavailability to CNS to >10%
• Secreted in urine unchanged or conjugated with glucuronyl sulfate

Question 12

ADVERSE EFFECTS OF L-DOPA / DOPAMINE (AND DOPAMINE RECEPTOR AGONISTS)

Answer 12

The most common short-term side effects are nausea, headache, feeling dizzy, and feeling sleepy

-Nausea and vomiting (>80% on initiation)

• Dopamine activates emetic centers [Chemoreceptor
• Trigger Zone (CTZ)] in CNS
• Tachycardia, increased contractility, arrhythmias
• Stimulates β1 receptors in heart—>increases HR and force of contraction.
• Orthostatic hypotension (30%)
• Stimulates DA receptors in mesenteric and renal vascular beds–>

vasodilation.

-Behavioral disturbances (hallucinations, paranoia, mania, delusions, confusion)

Question 13

dopmaine agonist

Answer 13

ergot

Bromocriptine (D2)

Cabergoline (D2)

Pergolide (D1/D2)

non-ergot

Pramipexole (D3/D2)

Ropinirole (D3/D2)

Question 14

DISTINGUISHING FEATURES ANDADVANTAGES

Answer 14

Directly stimulate dopamine receptors

No metabolic conversion

No absorption delay from competition with dietary amino acids

Longer half-life than levodopa
Can be used as monotherapy or adjunctive

therapy with levodopa and other medications

May delay or reduce motor fluctuations & dyskinesias associated with levodopa therapy

Contraindicated in patients with history of psychosis

Question 15

whichDopamine Agonists drug

Also used for neuroleptic malignant syndrome…

• See with typical antipsychotics
• Approved for use in Diabetes

Answer 15

Bromocriptine (Parlodel®)

Question 16

which dopamine agonist drug

voluntarily discontinued in US due to cardiac valve disorders

Answer 16

Pergolide (Permax®)

•Pergolide voluntarily discontinued in US due to cardiac valve disorders

Question 17

Non-Ergot Derived Dopamine agonists

Answer 17

Ropinirole (Requip®)- ORAL

• Pramipexole (Mirapex®) ORAL
• Rotigotine (Neupro®)-Patch

Apomorphine (Apokyn) injector

Question 18

ROTIGOTINE (NEUPRO®)

Answer 18

Neupro is a non-ergoline D3/D2/D1 dopamine agonist, which uses a transdermal delivery system for continuous delivery over a 24-hour period.

Neupro was removed due to reports of rotigotine crystals forming in the patches. The formation of rotigotine crystals results in reduced absorption and altered efficacy

-Approved for use in patients with early-stage PD

side effects : Nausea and vomiting, dizziness, somnolence, headache, insomnia, extremity edema (e.g. swollen hands and feet), and application site reactions.

Question 19

APOMORPHINE (APOKYN®)

Answer 19

-POTENT mixed agonist at D

Treatment of unpredictable, frequent motor fluctuations

 Supplied pen injection system

• Dose of Apokyn must be titrated and started in medical office
• SE: nausea, vomiting, hypotension

Question 20

DOPAMINE AGONISTS: COMMON ADVERSE EFFECTS

Answer 20

Not as effective as L-dopa and most patients will eventually require L-dopa supplementation.

 Nausea, vomiting

 Dizziness, postural hypotension, lower limb edema

 Headache, confusion, hallucinations, paranoia

 Drowsiness & somnolence

 Dyskinesias

Erythromelalgia; pulmonary & peritoneal fibrosis; pleural effusion & pleural thickening; Raynaud’s phenomena.

Question 21

ERYTHROMELALGIA & RAYNAUD’S PHENOMENON

Answer 21

Erythromelalgia: Neurovascular peripheral pain disorder in which blood vessels in the lower extremities are episodically blocked, then become hyperemic and inflamed, resulting in severe burning pain and skin redness.

raynaud: Disorder causing discoloration of fingers, toes, and other areas, believed to be the result of vasospasms that decrease blood supply and hypoxia of the affected areas

Question 22

____ and ___ increase bioavailability of L-DOPA to the CNS

Answer 22

decarboxylase and COMT

Question 23

CATECHOLAMINE INACTIVATION: ROLE OF DEGRADING ENZYMES

Answer 23

COMT inhibitors block peripheral metabolism of levodopa and increases its bioavailability to the CNS in Parkinson’s disease

Question 24

CATECHOL-O-METHYL TRANSFERASE(COMT) INHIBITORS

Answer 24

COMT inhibitors are medicines taken with levodopa that help levodopa work longer and better

 Utilized primarily to treat people whose levodopa “wears off” before the next dose (motor fluctuations

Question 25

ENTACAPONE (COMTAN®)

Answer 25

Increases “on time” by ~10%; Greater improvement in patients with the least amount of “on time”

 Available as Stalevo combination tablet (L- DOPA; Carbidopa and Entacapone)

 Dose adjustments for L-DOPA may be necessary depending on prior therapy

 Does not enter the CNS

Side effects: nausea, dyskinesia/hyperkinesia, diarrhea, abdominal pain, urine discoloration.

Question 26

TOLCAPONE (TASMAR®)

Answer 26

First COMT inhibitor licensed in the U.S.

 Reduced LD dosage by 12%, improved motor fluctuations by 14%

 “On time” increased >1.5 hrs/day  Improvements in QOL measures

 Enters CNS, but not the primary action

Side effects: Dizziness, orthostasis,diarrhea,

dyskinesias, confusion

 Acute fulminant hepatic necrosis

Question 27

SELECTIVE MAO-B INHIBITORS

Answer 27

• Selective irreversible inhibitors of MAO-B
• Monotherapy oradjunct
• Adverse effects include nausea, dizziness, abdominal pain, confusion, and exacerbation of L-DOPA side effects
• Tyramine consumption and MAO not as big an issue due to selectivity for MAO-B vs non- or MAO-A selective agents

Question 28

SELEGILINE (ELDEPRYL®)

Answer 28

Selegiline is an irreversible monoamine oxidase-B (MAO-B) inhibitor (dose-dependent selectivity)

 Primarily used as adjunctive therapy with L-DOPA

Question 29

SELEGILINE (ELDEPRYL VS ZELAPAR)

Answer 29

Eldepryl:
• Metabolized by CYP enzymes to

amphetamines/methamphetamines
• Dosed BID at breakfast and lunch with carbidopa/L-

DOPA
• Can contribute to agitation

Zelapar:

Once daily dosing

ODT that bypasses liver decreases/limits

amphetamine formation
• Faster onset of action, improved bioavailability (80%)

and tolerability

Question 30

RASAGILINE (AZILECT®)

Answer 30

Newer agent: Rasagiline is a selective irreversible MAO-B inhibitor; can be used as monotherapy early or as add-on later

CYP1A2 substrate
 No amphetamine like metabolites, so improved tolerability

 On-Off effect: Oscillations in response and sudden changes in mobility from no symptoms to full Parkinsonian symptoms in a matter of minutes

Decreases “off” time for patients on stable doses of carbidopa/levodopa

Question 31

ANTI-CHOLINERGICS

Answer 31

Dopaminergic Depletion –> Cholinergic Overactivity

 Historically the first therapies used for treatment of PD

 Effective for mild symptoms (mainly for tremor);

reserved for younger patients; avoid use in elderly patients

 Monotherapy or adjunct

 Common agents (Start low, go slow): Benztropine (Cogentin®) Trihexyphenidyl (Artane)®

Side effects (anti-SLUD and CNS effects):

 Dry mouth, constipation, urinary retention, sedation, blurred vision, and increased intraocular pressure; delirium, confusion, memory impairment, hallucinations, delusions

Question 32

AMANTADINE (SYMMETREL®)

Answer 32

Antiviral agent; PD benefit found accidentally

• Best for early stage, short term therapy

 Side effects — autonomic, psychiatric, livedo reticularis

Exact mechanism unknown but possibly related to:
 Enhancing release of stored dopamine

 inhibiting presynaptic reuptake of catecholamines

 Dopamine receptor agonist

 Weak, non-competitive NMDA receptor antagonist

 Although not shown to possess anticholinergic activity, it exhibits anticholinergic-like side effects

Dry mouth, urinary retention, and constipation